Cardiac stress testing is an important and widely used test for diagnosis of cardiovascular dysfunctions, particularly coronary heart disease. Cardiac stress testing is carried out to investigate how the cardiovascular system, particularly the heart, performs during exercise. In a typical example, the individual is asked to walk on a treadmill or to ride a stationary bike while diagnostic parameters such as an electrocardiogram or an echocardiogram are recorded. The exercise can also be simulated by administering drugs such as dobutamine or adenosine. The test is routinely carried out by general practitioners and local cardiologists.
Most individuals undergo cardiac stress testing without experiencing any problems. However, a considerable number of individuals develops serious cardiovascular adverse events such as myocardial infarction as a consequence of the test (see Pina, I. L., Balady, G. J., Hanson, P., et al. (1995) Guidelines for Clinical Exercise Testing Laboratories. Circulation, vol. 91, 912-921). These adverse events may even be fatal or near-fatal. Even non-fatal adverse events, such as non-fatal myocardial infarction, can have serious consequences, as the tissue of the muscle destroyed due to infarction can not be regenerated. Thus, a severe impairment of heart function and a disposition for further infarction or adverse events may remain and stress testing carries considerable risk for the individual.
One approach to make stress testing safer would be to perform the test exclusively in a clinical setting, and to have a physician trained in advanced cardiac life support ready for intervention. Indeed, such recommendations have been made (see Pina, I. L., Balady, G. J., Hanson, P., et al. (1995), Circulation, vol. 91, cited above). However, such a setting is not available everywhere and such precautions do not only increase the resources required for the test, but they may also cause undesirably long waiting lists and delay in scheduling an appointment for stress testing. Such a delay may itself carry a risk, as important diagnosis is delayed.
Currently, only individuals with a known history of relevant heart disease are referred to a clinical setting, because such individuals appear to be at risk of overstraining an already severely impaired organ during the test. Thus, there are still individuals undergoing stress testing in an unsafe environment who experience adverse events.
In some cases, parameter of heart function, e.g., echocardiogram, are measured before the test is carried out, in order to detect a relevant cardiac dysfunction. However, such measurements appear to be insufficient, as many cardiac dysfunctions remain undetected by echocardiography.
In some cases, levels of troponin T, creatine kinase (CK) or myoglobin are determined to exclude the presence of myocardial necrosis at the time of testing. However, these tests will detect only severe cardiac disease.
Foote et al. measured the levels of natriuretic peptides BNP and NT-proBNP in patients undergoing exercise stress testing before and after exercise stress testing (Foote, R. S., Pearlman, J. D., Siegel, A. H., Yeo, K-T. J. (2004). Detection of Exercise-Induced Ischemia by Changes in B-Type Natriuretic Peptides. Journal of the American College of Cardiology, vol. 44, no. 10., pp. 1980-1987). Foote et al. correlated the levels before and after the test with the presence or absence of myocardial ischemia during the stress test. However, only patients with already known coronary artery disease were enrolled in the study. Furthermore, only patients with resting levels of NT-proBNP and BNP within the normal range were enrolled. Thus the study did not allow a conclusion whether NT-proBNP and BNP allow stratifying individuals according to their risk of suffering from an adverse event during stress testing.
Weber et al. analyzed the levels of NT-proBNP in patients with stable angina pectoris before and after exercise stress testing (Weber, M., Dill, T., Arnold, R., Rau, M., et al. (2004). N-terminal B-type natriuretic peptide predicts extent of coronary artery disease and ischemia in patients with stable angina pectoris. Am Heart J, vol. 148, pp. 612-20). They found that within their patient sample, the levels of NT-proBNP were elevated in those patients with inducible ischemia as compared to those patients without inducible ischemia (396 pg/ml versus 160 pg/ml) during stress testing.
Sabatine et al. examined circulating BNP, NT-proBNP and NT-proANP levels before and after exercise stress testing (Sabatine, M. S., Morrow, D. A., de Lemos, J. A., Omland, T., Desai, M. Y., et al. (2004). Acute Changes in Circulating Natriuretic Peptide Levels in Relation to Myocardial Ischemia. Journal of the American College of Cardiology, vol. 44, no. 10, pp. 1988-95). They found that within their patient sample, the levels of NT-proBNP correlated with the no ischemia, mild-to-moderate ischemia and severe ischemia. Similar findings were made for BNP and NT-proANP.
The studies mentioned have focused on particular natriuretic peptides and the presence or absence of ischemia during stress testing. However, the levels found in these studies differed considerably, leaving it doubtful whether natriuretic peptides alone will allow a sufficiently reliable prediction of the appearing of ischemia during stress testing.
Thus, in the state of the art, there appears to be no method particularly suited to determine a risk whether an individual will suffer from a cardiovascular adverse event as a consequence of cardiac stress testing. Furthermore, there is a need for methods and uses to stratify individuals according to their risk of suffering from a cardiovascular adverse event as a consequence of cardiac stress testing.